Benzenoid derivatives of 15-hydroxyeicosatetraenoic acid and methods of their use in treating dry eye disorders

ABSTRACT

Benzenoid HETE derivatives and methods of their use for treating dry eye are disclosed.

This application claims priority to co-pending U.S. ProvisionalApplication, U.S. Serial No. 60/164,372 filed Nov. 9, 1999.

The present invention is directed to novel hydroxyeicosatetraenoic acidrelated compounds, compositions and methods of use. The compounds areparticularly useful in treating dry eye.

BACKGROUND OF THE INVENTION

Dry eye, also known generically as keratoconjunctivitis sicca, is acommon ophthalmological disorder affecting millions of Americans eachyear. The condition is particularly widespread among post-menopausalwomen due to hormonal changes following the cessation of fertility. Dryeye may afflict an individual with varying severity. In mild cases, apatient may experience burning, a feeling of dryness, and persistentirritation such as is often caused by small bodies lodging between theeye lid and the eye surface. In severe cases, vision may besubstantially impaired. Other diseases, such as Sjogren's disease andcicatricial pemphigoid manifest dry eye complications.

Although it appears that dry eye may result from a number of unrelatedpathogenic causes, all presentations of the complication share a commoneffect, that is the breakdown of the pre-ocular tear film, which resultsin dehydration of the exposed outer surface and many of the symptomsoutlined above (Lemp, Report of the National Eye Institute/IndustryWorkshop on Clinical Trials in Dry Eyes, The CLAO Journal, volume 21,number 4, pages 221-231 (1995)).

Practitioners have taken several approaches to the treatment of dry eye.One common approach has been to supplement and stabilize the ocular tearfilm using so-called artificial tears instilled throughout the day.Other approaches include the use of ocular inserts that provide a tearsubstitute or stimulation of endogenous tear production.

Examples of the tear substitution approach include the use of buffered,isotonic saline solutions, aqueous solutions containing water solublepolymers that render the solutions more viscous and thus less easilyshed by the eye. Tear reconstitution is also attempted by providing oneor more components of the tear film such as phospholipids and oils.Phospholipid compositions have been shown to be useful in treating dryeye; see, e.g., McCulley and Shine, Tear film structure and dry eye,Contactologia, volume 20(4), pages 145-49 (1998); and Shine andMcCulley, Keratoconjunctivitis sicca associated with meibomian secretionpolar lipid abnormality, Archives of Ophthalmology, volume 116(7), pages849-52 (1998). Examples of phospholipid compositions for the treatmentof dry eye are disclosed in U.S. Pat. No. 4,131,651 (Shah et al.), U.S.Pat. No. 4,370,325 (Packman), U.S. Pat. No. 4,409,205 (Shively), U.S.Pat. No. 4,744,980 and U.S. Pat. No. 4,883,658 (Holly), U.S. Pat. No.4,914,088 (Glonek), U.S. Pat. No. 5,075,104 (Gressel et al.), U.S. Pat.No. 5,278,151 (Korb et al.), U.S. Pat. No. 5,294,607 (Glonek et al.),U.S. Pat. No. 5,371,108 (Korb et al.) and U.S. Pat. No. 5,578,586(Glonek et al.). U.S. Pat. No. 5,174,988 (Mautone et al.) disclosesphospholipid drug delivery systems involving phospholipids, propellantsand an active substance.

U.S. Pat. No. 3,991,759 (Urquhart) discloses the use of ocular insertsin the treatment of dry eye. Other semi-solid therapy has included theadministration of carrageenans (U.S. Pat. No. 5,403,841, Lang) which gelupon contact with naturally occurring tear film.

Another approach involves the provision of lubricating substances inlieu of artificial tears. For example, U.S. Pat. No. 4,818,537 (Guo)discloses the use of a lubricating, liposome-based composition, and U.S.Pat. No. 5,800,807 (Hu et al.) discloses compositions containingglycerin and propylene glycol for treating dry eye.

Aside from the above efforts, which are directed primarily to thealleviation of symptoms associated with dry eye, methods andcompositions directed to treatment of the dry eye condition have alsobeen pursued. For example, U.S. Pat. No. 5,041,434 (Lubkin) disclosesthe use of sex steroids, such as conjugated estrogens, to treat dry eyecondition in post-menopausal women; U.S. Pat. No. 5,290,572 (MacKeen)discloses the use of finely divided calcium ion compositions tostimulate pre-ocular tear film production; and U.S. Pat. No. 4,966,773(Gressel et al.) discloses the use of microfine particles of one or moreretinoids for ocular tissue normalization.

Although these approaches have met with some success, problems in thetreatment of dry eye nevertheless remain. The use of tear substitutes,while temporarily effective, generally requires repeated applicationover the course of a patient's waking hours. It is not uncommon for apatient to have to apply artificial tear solution ten to twenty timesover the course of the day. Such an undertaking is not only cumbersomeand time consuming, but is also potentially very expensive. Transientsymptoms of dry eye associated with refractive surgery have beenreported to last in some cases from six weeks to six months or morefollowing surgery.

The use of ocular inserts is also problematic. Aside from cost, they areoften unwieldy and uncomfortable. Further, as foreign bodies introducedin the eye, they can be a source of contamination leading to infections.In situations where the insert does not itself produce and deliver atear film, artificial tears must still be delivered on a regular andfrequent basis.

Mucins are proteins which are heavily glycosylated withglucosamine-based moieties. Mucins provide protective and lubricatingeffects to epithelial cells, especially those of mucosal membranes.Mucins have been shown to be secreted by vesicles and discharged on thesurface of the conjunctival epithelium of human eyes (Greiner et al.,Mucous Secretory Vesicles in Conjunctival Epithelial Cells of Wearers ofContact Lenses, Archives of Ophthalmology, volume 98, pages 1843-1846(1980); and Dilly et al., Surface Changes in the Anaesthetic Conjunctivain Man, with Special Reference to the Production of Mucous from aNon-Goblet-Cell Source, British Journal of Ophthalmology, volume 65,pages 833-842 (1981)). A number of human-derived mucins which reside inthe apical and subapical corneal epithelium have been discovered andcloned (Watanabe et al., Human Corneal and Conjunctival EpitheliaProduce a Mucin-Like Glycoprotein for the Apical Surface, InvestigativeOphthalmology and Visual Science, volume 36, number 2, pages 337-344(1995)). Recently, Watanabe discovered a new mucin which is secreted viathe cornea apical and subapical cells as well as the conjunctivalepithelium of the human eye (Watanabe et al., IOVS, volume 36, number 2,pages 337-344 (1995)). These mucins provide lubrication, andadditionally attract and hold moisture and sebaceous material forlubrication and the corneal refraction of light.

Mucins are also produced and secreted in other parts of the bodyincluding lung airway passages, and more specifically from goblet cellsinterspersed among tracheal/bronchial epithelial cells. Certainarachidonic acid metabolites have been shown to stimulate mucinproduction in these cells. Yanni reported the increased secretion ofmucosal glycoproteins in rat lung by hydroxyeicosatetraenoic acid(“HETE”) derivatives (Yanni et al, Effect of Intravenously AdministeredLipoxygenase Metabolites on Rat Trachael Mucous Gel Layer Thickness,International Archives of Allergy And Applied Immunology, volume 90,pages 307-309 (1989)). Similarly, Marom has reported the production ofmucosal glycoproteins in human lung by HETE derivatives (Marom et al.,Human Airway Monohydroxy-eicosatetraenoic Acid Generation and MucousRelease, Journal of Clinical Investigation, volume 72, pages 122-127(1983)).

Agents claimed for increasing ocular mucin and/or tear productioninclude vasoactive intestinal polypeptide (Dartt et. al., Vasoactiveintestinal peptide-stimulated glycocongjugate secretion fromconjunctival goblet cells, Experimental Eye Research, volume 63, pages27-34, (1996)), gefarnate (Nakmura et. al., Gefarnate stimulatessecretion of mucin-like glycoproteins by corneal epithelium in vitro andprotects corneal epithelium from dessication in vivo, Experimental EyeResearch, volume 65, pages 569-574 (1997)), liposomes (U.S. Pat. No.4,818,537), androgens (U.S. Pat. No. 5,620,921), melanocycte stimulatinghormones (U.S. Pat. No. 4,868,154), phosphodiesterase inhibitors (U.S.Pat. No. 4,753,945), and retinoids (U.S. Pat. No. 5,455,265). However,many of these compounds or treatments suffer from a lack of specificity,efficacy and potency and none of these agents have been marketed so faras therapeutically useful products to treat dry eye and related ocularsurface diseases.

U.S. Pat. No. 5,696,166 (Yanni et al.) discloses compositions containingnaturally occurring HETEs, or derivatives thereof, and methods of usefor treating dry eye. Yanni et al. discovered that compositionscomprising HETEs increase ocular mucin secretion when administered to apatient and are thus useful in treating dry eye.

Prostaglandin-like molecules containing a benzene ring have beendisclosed in: Perchonock et. al., Prostaglandins, volume 15(4), pages623 (1978) (Formula II),

wherein the compounds disclosed were reported to inhibit prostaglandinsynthetase (cyclooxygenase); Kienzle et. al., Helv. Chim. Acta, volume63(6), page 1425 (1980) (Formula III), wherein the compounds disclosedwere reported to inhibit blood platelet aggregation and gastricsecretion; and U.S. Pat. No. 5,369,127 (Burk et al.), and continuationspatents (Formula IV), wherein the compounds disclosed were claimed tolower intraocular pressure.

In view of the foregoing, there is a need for an effective, conveninenttreatment for dry eye that is capable of alleviating symptoms, as wellas treating the underlying physical and physiological deficiencies ofdry eye.

SUMMARY OF THE INVENTION

The present invention is directed to compounds, compositions and methodsof use. The present invention is particularly directed to compositionsand methods for the treatment of dry eye and other disorders requiringthe wetting of the eye, including symptoms of dry eye associated withrefractive surgery such as LASIK surgery. More specifically, the presentinvention discloses ophthalmic compositions containing derivatives of(5Z,8Z, 11Z,13E)-15-hydroxyeicosa-5,8,11,13-tetraenoic acid (15-HETE) inwhich the Δ^(8,9:11,12) dienyl system is replaced by a benzene ring, andmethods using the same for treating dry eye type disorders. Thecompositions are preferably administered topically to the eye.

The compounds of the present invention are believed to be more stablethan the naturally occurring HETE-related compounds.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to novel benzenoid 15-HETEderivatives, compositions and methods of use. It is believed that, amongother utilities, the compounds stimulate ocular mucin production and/orsecretion following topical ocular application and are thereforebelieved to be useful in treating dry eye. These compounds are offormula I:

wherein:

R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂, CH₂SR²⁰,COSR²¹ or 2,3,4,5-tetrazol-1-yl, wherein:

R is H or CO₂R forms a pharmaceutically acceptable salt or apharmaceutically acceptable ester;

NR²R³ and NR⁵R⁶ are the same or different and comprise a free orfunctionally modified amino group, e.g., R², R³, R⁵ and R⁶ are the sameor different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH or alkoxy,with the proviso that at most only one of R² and R³ are OH or alkoxy andat most only one of R⁵ and R⁶ are OH or alkoxy;

OR⁴ comprises a free or functionally modified hydroxy group, e.g., R⁴ isH, acyl; alkyl, cycloalkyl, aralkyl or aryl;

Hal is F, Cl, Br or I;

SR²⁰ comprises a free or functionally modified thiol group;

R²¹ is H or COSR²¹ forms a pharmaceutically acceptable salt or apharmaceutically acceptable thioester;

X is C₂-C₅ alkyl, alkynyl, or alkenyl or a C₃-C₅ allenyl group;

Y is H, free or functionally modified hydroxy group, halo,trihalomethyl, free or functionally modified amino group, free orfunctionally modified thiol group, C(O)R⁷, or alkyl;

R⁷ is H, OH, alkyl, alkoxy, amino, alkylamino or alkoxyamino;

A is a direct bond or C₁₋₃ alkyl;

B is CH₂CH₂, cis- or trans-CH═CH, or C≡C; and

one of D and D¹ is H and the other is a free or functionally modified OHgroup, or DD¹ together comprises a double bonded oxygen.

To the best of our knowledge all of the compounds of the presentinvention are novel with the exception of compounds of formula II(Perchonock et. al., Prostaglandins, volume 15(4), pages 623 (1978)):

wherein R²⁵ is H or methyl.

The compounds of formula (I) may also be incorporated into phospholipidsas glyceryl esters or sphingomyelin amides. Phospholipid sphingomyelinamides of the compounds of formula (I) will typically comprise a formula(I) compound amidated via its carbon 1 carboxylate to the amino group ofthe sphingomyelin backbone. The phospholipid formula (I) esters willcomprise various phospholipids. Phospholipid esters of the compounds offormula (I) will typically comprise a formula (I) compound esterifiedvia its carbon 1 carboxylate to the sn-1 or sn-2 position alcohol, orboth, of the glycerol backbone of the phospholipid. If the sn-1 or sn-2position of the glyceryl ester class does not contain an ester of acompound of formula (I), then such carbon positions of the glycerolbackbone will comprise a methylene, ether or ester moiety linked to asubstituted or unsubstituted C₁₂₋₃₀ alkyl or alkenyl (the alkenyl groupcontaining one or more double bonds); alkyl(cycloalkyl)alkyl;alkyl(cycloalkyl); alkyl(heteroaryl); alkyl(heteroaryl)alkyl; oralkyl-M—Q; wherein the substitution is alkyl, halo, hydroxy, orfunctionally modified hydroxy; M is O or S; and Q is H, alkyl,alkyl(cycloalkyl)alkyl, alkyl(cycloalkyl), alkyl(heteroaryl) oralkyl(heteroaryl)alkyl. However, at least one of the sn-1 or sn-2position alcohols of the glycerol backbone must form an ester with acompound of formula (I) via the carbon 1 carboxylate of the latter.Preferred phospholipid-formula (I) esters will be of thephosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, andphospatidylinositol type. The most preferred phospholipid-formula (I)esters will comprise a formula (I) compound esterified via its carbon 1carboxylate to the alcohol at the sn-2 position of phosphatidylcholine,phosphatidylethanolamine or phosphatidylinositol. Thephospholipid-formula (I) esters and sphingomyelin amides may besynthesized using various phospholipid synthetic methods known in theart; see for example, Tsai et al., Biochemistry, volume 27, page 4619(1988); and Dennis et al., Biochemistry, volume 32, page 10185 (1993).

Included within the scope of the present invention are the individualenantiomers of the compounds of the present invention, as well as theirracemic and non-racemic mixtures. The individual enantiomers can beenantioselectively synthesized from the appropriate enantiomericallypure or enriched starting material by means such as those describedbelow. Alternatively, they may be enantioselectively synthesized fromracemic/non-racemic or achiral starting materials. (AsymmetricSynthesis; J. D. Morrison and J. W. Scott, Eds.; Academic PressPublishers: New York, 1983-1985, volumes 1-5; Principles of AsymmetricSynthesis; R. E. Gawley and J. Aube, Eds.; Elsevier Publishers:Amsterdam, 1996). They may also be isolated from racemic and non-racemicmixtures by a number of known methods, e.g. by purification of a sampleby chiral HPLC (A Practical Guide to Chiral Separations by HPLC; G.Subramanian, Ed.; VCH Publishers: New York, 1994; Chiral Separations byHPLC; A.M. Krstulovic, Ed.; Ellis Horwood Ltd. Publishers, 1989), or byenantioselective hydrolysis of a carboxylic acid ester sample by anenzyme (Ohno, M.; Otsuka, M. Organic Reactions, volume 37, page 1(1989)). Those skilled in the art will appreciate that racemic andnon-racemic mixtures may be obtained by several means, including withoutlimitation, nonenantioselective synthesis, partial resolution, or evenmixing samples having different enantiomeric ratios. Departures may bemade from such details within the scope of the accompanying claimswithout departing from the principles of the invention and withoutsacrificing its advantages. Also included within the scope of thepresent invention are the individual isomers substantially free of theirrespective enantiomers.

As used herein, the terms “pharmaceutically acceptable salt”,“pharmaceutically acceptable ester” and pharmaceutically acceptablethioester” means any salt, ester or thioester, respectively, that wouldbe suitable for therapeutic administration to a patient by anyconventional means without significant deleterious health consequences;and “ophthalmically acceptable salt”, “ophthalmically acceptable ester”and “ophthalmically acceptable thioester” means any pharmaceuticallyacceptable salt, ester or thioester, respectively, that would besuitable for ophthalmic application, i.e. non-toxic and non-irritating.

The term “free hydroxy group” means an OH. The term “functionallymodified hydroxy group” means an OH which has been functionalized toform: an ether, in which an alkyl, aryl, cycloalkyl, heterocycloalkyl,alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, or heteroaryl groupis substituted for the hydrogen; an ester, in which an acyl group issubstituted for the hydrogen; a carbamate, in which an aminocarbonylgroup is substituted for the hydrogen; or a carbonate, in which anaryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-, heterocycloalkoxy-,alkenyloxy-, cycloalkenyloxy-, heterocycloalkenyloxy-, oralkynyloxy-carbonyl group is substituted for the hydrogen. Preferredmoieties include OH, OCH₂C(O)CH₃,OCH₂C(O)C₂H₅, OCH₃, OCH₂CH₃, OC(O)CH₃,and OC(O)C₂H₅.

The term “free amino group” means an NH₂. The term “functionallymodified amino group” means an NH₂ which has been functionalized toform: an aryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-,heterocycloalkoxy-, alkenyl-, cycloalkenyl-, heterocycloalkenyl-,alkynyl-, or hydroxy-amino group, wherein the appropriate group issubstituted for one of the hydrogens; an aryl-, heteroaryl-, alkyl-,cycloalkyl-, heterocycloalkyl-, alkenyl-, cycloalkenyl-,heterocycloalkenyl-, or alkynyl-amino group, wherein the appropriategroup is substituted for one or both of the hydrogens; an amide, inwhich an acyl group is substituted for one of the hydrogens; acarbamate, in which an aryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-,heterocycloalkoxy-, alkenyl-, cycloalkenyl-, heterocycloalkenyl-, oralkynyl-carbonyl group is substituted for one of the hydrogens; or aurea, in which an aminocarbonyl group is substituted for one of thehydrogens. Combinations of these substitution patterns, for example anNH₂ in which one of the hydrogens is replaced by an alkyl group and theother hydrogen is replaced by an alkoxycarbonyl group, also fall underthe definition of a functionally modified amino group and are includedwithin the scope of the present invention. Preferred moieties includeNH₂, NHCH₃, NHC₂H₅, N(CH₃)₂, NHC(O)CH₃, NHOH, and NH(OCH₃).

The term “free thiol group” means an SH. The term “functionally modifiedthiol group” means an SH which has been functionalized to form: athioether, where an alkyl, aryl, cycloalkyl, heterocycloalkyl, alkenyl,cycloalkenyl, heterocycloalkenyl, alkynyl, or heteroaryl group issubstituted for the hydrogen; or a thioester, in which an acyl group issubstituted for the hydrogen. Preferred moieties include SH, SC(O)CH₃,SCH₃, SC₂H₅, SCH₂C(O)C₂H₅, and SCH₂C(O)CH₃.

The term “acyl” represents a group that is linked by a carbon atom thathas a double bond to an oxygen atom and a single bond to another carbonatom.

The term “alkyl” includes straight or branched chain aliphatichydrocarbon groups that are saturated and have 1 to 15 carbon atoms. Thealkyl groups may be interrupted by one or more heteroatoms, such asoxygen, nitrogen, or sulfur, and may be substituted with other groups,such as halogen, hydroxyl, aryl, cycloalkyl, aryloxy, or alkoxy.Preferred straight or branched alkyl groups include methyl, ethyl,propyl, isopropyl, butyl and t-butyl.

The term “cycloalkyl” includes straight or branched chain, saturated orunsaturated aliphatic hydrocarbon groups which connect to form one ormore rings, which can be fused or isolated. The rings may be substitutedwith other groups, such as halogen, hydroxyl, aryl, aryloxy, alkoxy, orlower alkyl. Preferred cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl.

The term “heterocycloalkyl” refers to cycloalkyl rings that contain atleast one heteroatom such as O, S, or N in the ring, and can be fused orisolated. The rings may be substituted with other groups, such ashalogen, hydroxyl, aryl, aryloxy, alkoxy, or lower alkyl. Preferredheterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl,piperazinyl, and tetrahydropyranyl.

The term “alkenyl” includes straight or branched chain hydrocarbongroups having 1 to 15 carbon atoms with at least one carbon-carbondouble bond, the chain being optionally interrupted by one or moreheteroatoms. The chain hydrogens may be substituted with other groups,such as halogen. Preferred straight or branched alkenyl groups includeallyl, 1-butenyl, 1-methyl-2-propenyl and 4-pentenyl.

The term “cycloalkenyl” includes straight or branched chain, saturatedor unsaturated aliphatic hydrocarbon groups which connect to form one ormore non-aromatic rings containing a carbon-carbon double bond, whichcan be fused or isolated. The rings may be substituted with othergroups, such as halogen, hydroxyl, alkoxy, or lower alkyl. Preferredcycloalkenyl groups include cyclopentenyl and cyclohexenyl.

The term “heterocycloalkenyl” refers to cycloalkenyl rings which containone or more heteroatoms such as O, N, or S in the ring, and can be fusedor isolated. The rings may be substituted with other groups, such ashalogen, hydroxyl, aryl, aryloxy, alkoxy, or lower alkyl. Preferredheterocycloalkenyl groups include pyrrolidinyl, dihydropyranyl, anddihydrofuranyl.

The term “carbonyl group” represents a carbon atom double bonded to anoxygen atom, wherein the carbon atom has two free valencies.

The term “aminocarbonyl” represents a free or functionally modifiedamino group bonded from its nitrogen atom to the carbon atom of acarbonyl group, the carbonyl group itself being bonded to another atomthrough its carbon atom.

The term “lower alkyl” represents alkyl groups containing one to sixcarbons (C₁-C₆).

The term “halogen” represents fluoro, chloro, bromo, or iodo.

The term “aryl” refers to carbon-based rings which are aromatic. Therings may be isolated, such as phenyl, or fused, such as naphthyl. Thering hydrogens may be substituted with other groups, such as loweralkyl, halogen, free or functionalized hydroxy, trihalomethyl, etc.Preferred aryl groups include phenyl, 3-(trifluoromethyl)phenyl,3-chlorophenyl, and 4-fluorophenyl.

The term “heteroaryl” refers to aromatic hydrocarbon rings which containat least one heteroatom such as O, S, or N in the ring. Heteroaryl ringsmay be isolated, with 5 to 6 ring atoms, or fused, with 8 to 10 atoms.The heteroaryl ring(s) hydrogens or heteroatoms with open valency may besubstituted with other groups, such as lower alkyl or halogen. Examplesof heteroaryl groups include imidazole, pyridine, indole, quinoline,furan, thiophene, pyrrole, tetrahydroquinoline, dihydrobenzofuran, anddihydrobenzindole.

The terms “aryloxy”, “heteroaryloxy”, “alkoxy”, “cycloalkoxy”,“heterocycloalkoxy”, “alkenyloxy”, “cycloalkenyloxy”,“heterocycloalkenyloxy”, and “alkynyloxy” represent an aryl, heteroaryl,alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl,heterocycloalkenyl, or alkynyl group, respectively, attached through anoxygen linkage.

The terms “alkoxycarbonyl”, “aryloxycarbonyl”, “heteroaryloxycarbonyl”,“cycloalkoxycarbonyl”, “heterocycloalkoxycarbonyl”,“alkenyloxycarbonyl”, “cycloalkenyloxycarbonyl”,“heterocycloalkenyloxycarbonyl”, and “alkynyloxycarbonyl” represent analkoxy, aryloxy, heteroaryloxy, cycloalkoxy, heterocycloalkoxy,alkenyloxy, cycloalkenyloxy, heterocycloalkenyloxy, or alkynyloxy group,respectively, bonded from its oxygen atom to the carbon of a carbonylgroup, the carbonyl group itself being bonded to another atom throughits carbon atom.

Preferred compounds of the present invention include those of formula I,wherein:

R¹ is CO₂R, wherein R is H or CO₂R forms an ophthalmically acceptablesalt or an ophthalmically acceptable ester;

X is (CH₂)₄, CH═CHCH₂CH₂, CH₂CH═CHCH₂, C≡CCH₂CH₂ or CH₂C≡CCH₂;

Y is H, halo, trihalomethyl or alkyl;

A is a direct bond or CH₂;

B is CH₂CH₂, trans-CH═CH or C≡C; and one of D and D¹ is H and the otheris OH.

Among the particularly preferred compounds of formula (I) are thosewhose preparations are detailed in the following examples 1-3:

EXAMPLE 1

(5Z)-6-[2-(3R-hydroxy-1E-octenyl)-1-phenyl]hex-5-enoic acid (1)

Wittig condensation of lactol 4 [for the preparation of 4, see: J. Org.Chem., 55:3214 (1990)] with Ph₃P⁺(CH₂)₄CO₂H Br⁻ in tetrahydrofuran (THF)at 0° C. in the presence of potassium t-butoxide (KOBu^(t)), followed bytreatment of the resulting eneacid with ethereal CH₂N₂, affords methylester 5. Oxidation of 5 using catalytic tetra-n-propylammoniumperruthenate (TPAP) and stoichiometric N-methylmorpholine N-oxide (NMO)yields aldehyde 6, which is condensed with dimethyl2-oxoheptylphosphonate in the presence of NEt₃ and LiCl to give enone 7.Enone 7 is reduced with (−)-B-chlorodiisopinocampheylborane, followed bytreatment with KOH in THF/water to saponify the methyl ester, to afford1.

EXAMPLE 2

(5Z)-6-[3-(3R-hydroxy-1E-octenyl)-1-phenyl]hex-5-enoic acid (2)

Treatment of 3-hydroxybenzaldehyde (8) with trifluoromethanesulfonicanhydride (Tf₂O) in pyridine at 0° C. provides triflate 9, which iscoupled with (3R)-3-hydroxy-1-octyne [for the preparation of thiscompound, see: Midland et. al., Tetrahedron, 40:1371 (1984)] underSonogashira conditions [PdCl₂(PPh₃)₂, CuI, NEt₃, room temperature] togive alkyne 10. Reduction of 10 with Na₂[H₂Al(OCH₂CH₂OCH₃)₂] (Red-Al®)yields enediol 11, which is oxidized to hydroxyaldehyde 12 usingcatalytic 2,2,6,6-tetramethyl-N-piperidinoxyl free radical (TEMPO) andstoichiometric N-chlorosuccinimide (NCS). Wittig condensation of 12 withPh₃P⁺(CH₂)₄CO₂H Br⁻ in tetrahydrofuran (THF) at 0° C. in the presence ofKOBu^(t) affords 2 after purification.

EXAMPLE 3

(5Z)-6-[4-(3R-hydroxy-1E-octenyl)-1-phenyl]hex-5-enoic acid (3)

Treatment of 4-hydroxybenzaldehyde (13) with Tf₂O in pyridine at 0° C.provides triflate 14, which is coupled with (3R)-3-hydroxy-1-octyneunder Sonogashira conditions [PdCl₂(PPh₃)₂, CuI, NEt₃, room temperature]to give alkyne 15. Reduction of 15 with Red-Al® yields enediol 16, whichis oxidized to hydroxyaldehyde 17 using catalytic TEMPO andstoichiometric NCS. Wittig condensation of 17 with Ph₃P⁺(CH₂)₄CO₂H Br⁻in tetrahydrofuran (THF) at 0° C. in the presence of KOBu^(t) affords 3after purification.

Salt forms of the formula (I) compounds are preferred as it is believedthat the neat salts are more stable than the corresponding neat acids.Preferred salts of the present invention are those wherein a terminalcarboxylate of formula (I) (i.e., wherein R¹ is CO₂R) forms a salt withcations selected from: Na⁺, K⁺, NH₄ ⁺, benzyltrimethylammonium ion,tetrabutylammonium ion, and phenyltrimethyl ammonium ion.

As used hereinafter, the term “compounds of formula (I),” refers tocompounds of formula (I), and/or the phospholipid-formula (I) esters oramides described above. The compositions of the present inventioncomprise one or more compounds of formula (I) and a pharmaceuticallyacceptable carrier. The compositions are formulated in accordance withmethods known in the art for the particular route of administrationdesired for the prevention, treatment or amelioration of the particulardisease or disorder targeted. The level of peroxy compounds in the HETEderivative raw materials that are used to prepare the pharmaceuticalformulations of the present invention may have an impact on the HETEderivative's biological activity. Although the precise relationship hasnot been defined, it is preferable to use HETE derivative raw materialsupplies containing peroxy compounds at levels no greater than about 0.3ppm. Methods for determining peroxy levels are known in the art (e.g.,European Pharmacopoeia 1997 3^(rd) Ed., Method 2.5.5—Peroxide Value).

As used herein, the term “pharmaceutically acceptable carrier” refers toany formulation which is safe, and provides the appropriate delivery ofan effective amount of one or more compounds of formula (I) for theprevention, treatment or amelioration of the disease or disordertargeted.

As used herein, the term “pharmaceutically effective amount” refers toan amount of one or more compounds of formula (I) that, whenadministered to a patient, prevents, treats or ameliorates a disease ordisorder, or conditions associated thereof. As used herein, “anophthalmically effective amount” refers to an amount of one or morecompounds of formula (I) that, when administered to a patient, prevents,treats or ameliorates an ophthalmic disease or disorder, or conditionsassociated thereof. For the treatment of dry eye, such an effectiveamount will stimulate secretion of mucin in the eye and thus eliminateor improve dry eye conditions when administered to the eye. As usedherein, “an effective amount to treat dry eye” refers to an amount ofone or more compounds of formula (I) that, when administered to apatient, prevents, treats or ameliorates a dry eye disease or disorder,or conditions associated thereof. Generally, the compounds of formula(I) will be contained in a composition of the present invention in aconcentration range of about 0.00001 to 10 percent weight/volume (“%w/v”). Preferred ophthalmic, including dry eye-treatment, compositionswill contain one or more compounds of formula (I) in a concentration offrom about 0.00001-0.01% w/v.

The present invention is particularly directed to compositions useful intreating dry eye. Preferably, such compositions will be formulated assolutions, suspensions and other dosage forms for topicaladministration. Aqueous solutions are generally preferred, based on easeof formulation, biological compatibility (especially in view of themalady to be treated, e.g., dry eye-type diseases and disorders), aswell as a patient's ability to easily administer such compositions bymeans of instilling one to two drops of the solutions in the affectedeyes. However, the compositions may also be suspensions, viscous orsemi-viscous gels, or other types of solid or semi-solid compositions.Suspensions may be preferred for compounds of formula (I) which are lesssoluble in water.

Preferably, the ophthalmic compositions of the present invention willalso contain ethanol. As used herein, “an effective concentration ofethanol” refers to a concentration that enhances the biological efficacyof the formula (I) compositions in vivo. In general, the concentrationof ethanol necessary for the enhancement of the compounds of formula (I)is believed to be somewhat proportional to the concentration of theformula (I) compound(s) administered. If a relatively high concentrationof formula (I) compound(s), e.g., above 0.01% w/v, is administered, theconcentration of ethanol in such compositions may be proportionally lessthan analogous compositions containing lower concentrations of formula(I) compounds. In general, however, the ethanol concentration containedin the ophthalmic compositions of the present invention will range fromabout 0.001-2% w/v. Compositions containing formula (I) concentrationsof about 0.00001-0.02% w/v preferably will contain ethanol in aconcentration of about 0.005-0.2% w/v, and most preferably, about0.02-0.10% w/v.

Preferably, the compositions of the present invention will also containa surfactant. Various surfactants useful in topical ophthalmicformulations may be employed. The surfactant(s) may provide additionalchemical stabilization of the formula (I) compounds and may furtherprovide for the physical stability of the compounds. In other words, thesurfactants may aid in preventing chemical degradation of the compoundsof formula (I) and also prevent the compounds from binding to thecontainers in which their compositions are packaged. As used herein, “aneffective concentration of surfactant(s)” refers to a concentration thatenhances the chemical and physical stability of formula (I) compound(s).Examples of surfactants include, but are not limited to: Cremophor® EL,polyoxyl 20 ceto stearyl ether, polyoxyl 40 hydrogenated castor oil,polyoxyl 23 lauryl ether and poloxamer 407 may be used in thecompositions. A preferred surfactant is polyoxyl 40 stearate. Theconcentration of surfactant will vary, depending on the concentration offormula (I) compound(s) and optional ethanol present in the formulation.In general, however, the surfactant(s) concentration will be about 0.001to 2.0% w/v. Preferred compositions of the present invention willcontain about 0.1% w/v of polyoxyl 40 stearate.

The compositions of the present invention may also include various otheringredients, such as tonicity agents, buffers, preservatives,co-solvents and viscosity building agents.

Various tonicity agents may be employed to adjust the tonicity of thecomposition, preferably to that of natural tears for ophthalmiccompositions. For example, sodium chloride, potassium chloride,magnesium chloride, calcium chloride, dextrose and/or mannitol may beadded to the composition to approximate physiological tonicity. Such anamount of tonicity agent will vary, depending on the particular agent tobe added. In general, however, the compositions will have a tonicityagent concentration of about 0.1-1.5% w/v. Sodium chloride in the amountof 0.75% w/v is preferred.

An appropriate buffer system (e.g., sodium phosphate, sodium acetate,sodium citrate, sodium borate or boric acid) may be added to thecompositions to prevent pH drift under storage conditions. Theparticular concentration will vary, depending on the agent employed. Ingeneral, however, such a concentration will range from about 0.02 to2.0% w/v. Preferred compositions will contain about 0.25% w/v of boricacid.

Antioxidants may be added to compositions of the present invention toprotect the formula (I) compounds from oxidation during storage.Examples of such antioxidants include, but are not limited to, vitamin Eand analogs thereof, ascorbic acid and derivatives, and butylatedhydroxyanisole (BHA).

Compositions formulated for the treatment of dry eye-type diseases anddisorders may also comprise aqueous carriers designed to provideimmediate, short-term relief of dry eye-type conditions. Such carrierscan be formulated as a phospholipid carrier or an artificial tearscarrier, or mixtures of both. As used in this paragraph and theimmediately succeeding paragraph, the term “phospholipid” refers only tothe phospholipids of the phospholipid carrier, does not refer to acompound of formula (I) and, as such, does not contain a formula (I)compound. As used herein, “phospholipid carrier” and “artificial tearscarrier” refer to aqueous compositions which: (i) comprise one or morephospholipids (in the case of phospholipid carriers) or other compounds,which lubricate, “wet,” approximate the consistency of endogenous tears,aid in natural tear build-up, or otherwise provide temporary relief ofdry eye symptoms and conditions upon ocular administration; (ii) aresafe; and (iii) provide the appropriate delivery vehicle for the topicaladministration of an effective amount of one or more compounds offormula (I). Examples or artificial tears compositions useful asartificial tears carriers include, but are not limited to, commercialproducts, such as Tears Naturale®, Tears Naturale II®, Tears NaturaleFree®, and Bion Tears® (Alcon Laboratories, Inc., Fort Worth, Tex.).Examples of phospholipid carrier formulations include those disclosed inU.S. Pat. No. 4,804,539 (Guo et al.), U.S. Pat. No. 4,883,658 (Holly),U.S. Pat. No. 4,914,088 (Glonek), U.S. Pat. No. 5,075,104 (Gressel etal.), U.S. Pat. No. 5,278,151 (Korb et al.), U.S. Pat. No. 5,294,607(Glonek et al.), U.S. Pat. No. 5,371,108 (Korb et al.), U.S. Pat. No.5,578,586 (Glonek et al.); the foregoing patents are incorporated hereinby reference to the extent they disclose phospholipid compositionsuseful as phospholipid carriers of the present invention.

The phospholipids useful in the phospholipid carriers are any natural orsynthetic phospholipid compound comprising a glycerol-phosphoric acidester or sphingomyelin backbone. Examples of phospholipids useful in thepresent invention include those of formula (V):

wherein, X²¹ and X²² are the same or different and are O, NH(C═O),O(C═O), or a direct bond;

R²² is H or CH═CH(CH₂)₁₂CH₃;

X²¹—R¹ is OH, or R¹ is C₁₂₋₂₆ substituted or unsubstituted alkyl oralkenyl;

R² is C₁₂₋₂₆ substituted or unsubstituted alkyl or alkenyl; and

R³ is H, OH, OCH₂CH(NH₃ ⁺)COO⁻, OCH₂CH₂NH₃ ⁺, OCH₂CH₂N⁺(CH₃)₃,OCH₂CH(OH)CH₂OH and O-inositol.

The phospholipids may be present as racemic or non-racemic compounds.Preferred phospholipids are those wherein X²¹—R¹ and/or X²²—R² comprisefatty acid esters or amides. Natural fatty acids are saturated,monounsaturated or polyunsaturated. Examples of fatty acid residuesinclude, but are not limited to, laurate, myristate, palmitate,palmitoleate, stearate, oleate, linoleate, linolenate, eicosanoate,docosanoate and lignocerate. Preferred phospholipid types are thephosphatidylethanolamines, phosphatidylcholines, phosphatidylserines,phospatidylinositols and sphingomyelins. Examples of specificphospholipids include: 1,2-dipalmitoyl phosphatidyl choline (“DPPC”)1,2-dipalmityl phosphatidyl glycerol (“DPPG”), N-stearyl sphingomyelin,N-palmityl sphingomyelin, N-oleyl sphingomyelin, 1,2-distearoylphosphatidyl ethanolamine (“DSPE”), 1,2-distearoyl phosphatidyl inositol(“DSPI”), 1-stearoyl-2-palmitoyl phosphatidyl ethanolamine (“SPPE”),1-stearoyl-2-palmitoyl phosphatidyl choline (“SPPC”), 1,2-dipalmitoylphosphatidyl ethanolamine (“DPPE”), 1,2-dioleoyl phophatidylethanolamine (“DOPE”), 1,2-dioleoyl phophatidyl serine (“DOPS”), and1,2-dipalmitoyl phosphatidyl serine (“DPPS”). The most preferredphospholipid carriers are the phosphatidylethanolamines andsphingomyelins. Phospholipids are available from a variety of naturalsources and may be synthesized by methods known in the art; see, forexample, Tsai et al., Biochemistry, volume 27, page 4619 (1988); andDennis et. al., Biochemistry, volume 32, page 10185 (1993).

Other compounds designed to lubricate, “wet,” approximate theconsistency of endogenous tears, aid in natural tear build-up, orotherwise provide temporary relief of dry eye symptoms and conditionsupon ocular administration the eye are known in the art. Such compoundsmay enhance the viscosity of the composition, and include, but are notlimited to: monomeric polyols, such as, glycerol, propylene glycol,ethylene glycol; polymeric polyols, such as, polyethylene glycol,hydroxypropylmethyl cellulose (“HPMC”), carboxy methylcellulose sodium,hydroxy propylcellulose (“HPC”), dextrans, such as, dextran 70; watersoluble proteins, such as gelatin; and vinyl polymers, such as,polyvinyl alcohol, polyvinylpyrrolidone, povidone and carbomers, suchas, carbomer 934P, carbomer 941, carbomer 940, carbomer 974P.

Other compounds may also be added to the ophthalmic compositions of thepresent invention to increase the viscosity of the carrier. Examples ofviscosity enhancing agents include, but are not limited to:polysaccharides, such as hyaluronic acid and its salts, chondroitinsulfate and its salts, dextrans, various polymers of the cellulosefamily; vinyl polymers; and acrylic acid polymers. In general, thephospholipid carrier or artificial tears carrier compositions willexhibit a viscosity of 1 to 400 centipoises (“cps”). Preferredcompositions containing artificial tears or phospholipid carriers willexhibit a viscosity of about 25 cps.

Topical ophthalmic products are typically packaged in multidose form.Preservatives are thus required to prevent microbial contaminationduring use. Suitable preservatives include: benzalkonium chloride,chlorobutanol, benzododecinium bromide, methyl paraben, propyl paraben,phenylethyl alcohol, edetate disodium, sorbic acid, polyquaternium-1, orother agents known to those skilled in the art. Such preservatives aretypically employed at a level of from 0.001 to 1.0% w/v. Unit dosecompositions of the present invention will be sterile, but typicallyunpreserved. Such compositions, therefore, generally will not containpreservatives.

The preferred compositions of the present invention are intended foradministration to a human patient suffering from dry eye or symptoms ofdry eye. Preferably, such compositions will be administered topically.In general, the doses used for the above described purposes will vary,but will be in an effective amount to increase mucin production in theeye and thus eliminate or improve dry eye conditions. Generally, 1-2drops of such compositions will be administered 1-10 times per day forthe treatment of dry eye or other ocular disease or disorder.Preferably, 1-2 drops of the compositions will be administered 1-4 timesper day.

The present invention is also directed to stable, stock compositionscomprising one or more compounds of formula (I) and ethanol. Theinventors believe that storing the compounds of formula (I) in anethanolic solution provides greater stability of the compounds offormula (I) over analogous aqueous compositions, or neat compounds offormula (I) compositions. Such compositions comprise one or morecompounds of formula (I) and an amount of ethanol to solubilize thecompounds of formula (I) in solution. Preferably, the ethanolic stocksolutions will contain anhydrous ethanol, but aqueous ethanolicsolutions are also contemplated by the present invention. Generally, thestock solutions will contain ethanol in a concentration of about 25 to100% volume/volume (“v/v”). Typically, such stock solutions will containcompounds of formula (I) in high concentration relative to thepharmaceutical compositions of the present invention.

The following Examples 1-5 describe preferred compositions of thepresent invention. The actual pH of the compositions may vary (e.g.,between 6-8), and the concentrations of the various ingredients includedin the exemplified compositions may vary, but are included in thecompositions in the approximate amounts shown.

EXAMPLE 1

Ingredient Amount (% w/v) Compound 1 0.00001-0.01 Ethanol 0.0505Polyoxyl 40 Stearate 0.1 Boric Acid 0.25 Sodium Chloride 0.75 DisodiumEdetate 0.01 Polyquaternium-1 0.001 NaOH/HCl q.s., pH = 7.5 PurifiedWater q.s. 100%

The above composition is prepared by the following method. The batchquantities of polyoxyl 40 stearate, boric acid, sodium chloride,disodium edetate, and polyquatemium-1 are weighed and dissolved bystirring in 90% of the batch quantity of purified water. The pH isadjusted to 7.5±0.1 with NaOH and/or HCl. Under yellow light or reducedlighting, the batch quantity of Compound 1 as a stock solution inethanol and the additional quantity of ethanol necessary for the batchare measured and added. Purified water is added to q.s. to 100%. Themixture is stirred for five minutes to homogenize and then filteredthrough a sterilizing filter membrane into a sterile recipient.

Preferably, the above process is performed using glass, plastic or othernon-metallic containers or containers lined with such materials.

EXAMPLE 2

Ingredient Amount (% w/v) Compound of formula (I) 0.00001-0.01 Ethanol 0.005-0.2 Polyoxyl 40 Stearate 0.1 Boric Acid 0.25 Sodium Chloride 0.75Disodium Edetate 0.01 Polyquaternium-1 0.001 NaOH/HCl q.s., pH = 7.5Purified Water q.s. 100%

The above formulation may be made by a method similar to the methoddescribed in Example 1.

EXAMPLE 3

Ingredient Amount (% w/v) Compound of formula (I) 0.00001-0.01 Polyoxyl40 Stearate 0.1 Ethanol  0.005-0.2 Boric Acid 0.25 Sodium Chloride 0.75NaOH/HCl q.s., pH = 7.5 Purified Water q.s. 100%

The above formulation may be made by a method similar to the methoddescribed in Example 1.

EXAMPLE 4

The following is an example of an artificial tears carrier-compositionof the present invention:

Ingredient Amount (% w/v) Compound of formula (I) 0.00001-0.01 HPMC 0.3Dextran 70 0.1 Sodium Chloride 0.8 Potassium Chloride 0.12 DibasicSodium Phosphate 0.025 Disodium EDTA 0.01 Polyquaternium-1 0.001 + 10%excess Purified Water Qs NaOH/HCl qs to pH 6-8

The above formulation may be made by a method similar to the methoddescribed in Example 1.

EXAMPLE 5

The following is an example of a phospholipid carrier-composition of thepresent invention:

Ingredient Amount (% w/v) Compound of formula (I) 0.00001-0.01 Ethanol 0.005-0.2 Polyoxyl 40 Stearate 0.1 DPPC 0.05 DPPE 0.05 Sodium Chloride0.8 Potassium Chloride 0.12 Dibasic Sodium Phosphate 0.025 Disodium EDTA0.01 Polyquaternium-1 0.001 + 10% excess Purified Water Qs NaOH/HCl qsto pH 6-8

The above formulation may be made by a method similar to the methoddescribed in Example 1.

The invention in its broader aspects is not limited to the specificdetails shown and described above. Departures may be made from suchdetails within the scope of the accompanying claims without departingfrom the principles of the invention and without sacrificing itsadvantages.

What is claimed is:
 1. A composition for the treatment of dry eye andother disorders requiring the wetting of the eye comprising apharmaceutically acceptable carrier and a pharmaceutically effectiveamount of one or more compounds of the following formula I:

wherein: R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂,CH₂SR²⁰, COSR²¹ or 2,3,4,5-tetrazol-1-yl, wherein: R is H or CO₂R formsa pharmaceutically acceptable salt or a pharmaceutically acceptableester; NR²R³ and NR⁵R⁶ are the same or different and comprise a free orfunctionally modified amino group; OR⁴ comprises a free or functionallymodified hydroxy group; Hal is F, Cl, Br or l; SR²⁰ comprises a free orfunctionally modified thiol group; R²¹ is H or COSR²¹ forms apharmaceutically acceptable salt or a pharmaceutically acceptablethioester: X is C₂-C₅ alkyl, alkynyl, or alkenyl or a C₃-C₅ allenylgroup; Y is H, halo, trihalomethyl, free or functionally modified aminogroup, free or functionally modified thiol group, C(O)R⁷, or alkyl; R⁷is H, OH, alkyl, alkoxy, amino, alkylamino or alkoxyamino; A is a directbond or C₁₋₃ alkyl; B is CH₂CH₂, cis- or trans-CH═CH or C≡C; and one ofD and D¹ is H and the other is a free or functionally modified OH group,or DD¹ together comprises a double bonded oxygen.
 2. The composition ofclaim 1, wherein for the compound of formula I: R¹ is CO₂R, wherein R isH or CO₂R forms an ophthalmically acceptable salt or an ophthalmicallyacceptable ester; X is (CH₂)₄, CH═CHCH₂CH₂, CH₂CH═CHCH₂, C≡CCH₂CH₂ orCH₂C≡CCH₂; Y is H, halo, trihalomethyl, or alkyl; A is a direct bond orCH₂; B is CH₂CH₂, trans-CH═CH, or C≡C; and one of D and D¹ is H and theother is OH.
 3. The composition of claim 2, wherein the compound offormula (I) is selected from the group consisting of:


4. The composition of claim 1, wherein the composition is a topicalophthalmic formulation.
 5. A method for the treatment of dry eye andother disorders requiring the wetting of the eye which comprisesadministering to a mammal a composition comprising a pharmaceuticallyacceptable carrier and a pharmaceutically effective amount of one ormore compounds of the following formula I:

wherein: R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂,CH₂SR²⁰, COSR²¹ or 2,3,4,5-tetrazol-1-yl, wherein: R is H or CO₂R formsa pharmaceutically acceptable salt or a pharmaceutically acceptableester; NR²R³ and NR⁵R⁶ are the same or different and comprise a free orfunctionally modified amino group; OR⁴ comprises a free or functionallymodified hydroxy group; Hal is F, Cl, Br or I; SR²⁰ comprises a free orfunctionally modified thiol group; R²¹ is H or COSR²¹ forms apharmaceutically acceptable salt or a pharmaceutically acceptablethioester; X is C₂-C₅ alky, alkynyl, or alkenyl or a C₃-C₅ allenylgroup; Y is H, halo, trihalomethyl, free or functionally modified aminogroup, free or functionally modified thiol group. C(O)R⁷ or alkyl, R⁷ isH, OH, alkyl, alkoxy, amino, alkylamino or alkoxyamino; A is a directbond or C₁₋₃ alkyl; B is CH₂CH₂, cis- or trans-CH═CH or C≡C; and one ofD and D¹ is H and the other is a free or functionally modifiad OH group,or DD¹ together comprises a double bonded oxygen.
 6. The method of claim5, wherein for the compound of formula I: R¹ is CO₂R, wherein R is H orCO₂R forms an ophthalmically acceptable salt or an ophthalmicallyacceptable ester; X is (CH₂)₄, CH═CHCH₂CH₂, CH₂CH═CHCH₂, C≡CCH₂CH₂ orCH₂C≡CCH₂; Y is H, halo, trihalomethyl or alkyl; A is a direct bond orCH₂; B is CH₂CH₂, trans-CH═CH, or C≡C; and one of D and D¹ is H and theother is OH.
 7. The method of claim 6, wherein the compound of formula(I) is selected from the group consisting of:


8. The method of claim 5, wherein the composition is a topicalophthalmic formulation.
 9. The method of claim 5 wherein the dry eye andother disorders requiring the wetting of the eye is symptoms of dry eyeassociated with refractive surgery.
 10. A compound of the followingformula I;

wherein: R¹ is CO₂R, wherein R is H or CO₂R forms a pharmaceuticallyacceptable salt or a pharmaceutically acceptable ester; X is (CH₂)₄,CH═CHCH₂CH₂, CH₂CH═CHCH₂, C≡CCH₂CH₂ or CH₂C≡CCH₂; Y is H, halo,trihalomethyl or alkyl; A is a direct bond or CH₂; B is CH₂CH₂,trans-CH═CH or C≡C; and one of D and D¹ is H and the other is OH. 11.The compound of claim 10, wherein the compound of formula (I) isselected group consisting of: